The present invention is related to opioids and attention deficit hyperactivity disorder medications possessing abuse deterrent and anti-dose dumping safety features. More specifically, the present invention is related to bis-naphthyl bidentate organic salts having a carboxyl group and hydroxyl group in an ortho relationship to one another in each naphthyl ring and wherein only one of the substituted naphthyl rings is employed to form 1:1 salts of opioids and attention deficit hyperactivity disorder medications, their method of preparation of the salts, and enhanced drug products formulated therewith.
The ability to systematically impart abuse deterrent features to drug products via the drug substance component has been demonstrated within numerous U.S. Patents listed elsewhere herein. The unexpected findings associated with various organic acid salt forms of opiates, narcotics, stimulants and other amine-containing physiologically active and psychoactive drugs provides a universal approach to commercially revitalize a stable of useful medications while introducing additional features. Most pain and attention deficit hyperactivity disorder (ADHD) medications are subject to serious abuse which often leads to death of the abuser. No distinction is made herein between the recreational abuser and those that routinely abuse the medication. Whether as the free base, or in a salt form, the drug substance possesses the physiologically active portion of the drug product, and in the principal cases herein, constitutes a United States Drug Enforcement Administration “controlled substance”. Historically, the controlled substances are provided in highly soluble salt forms, and particularly highly water soluble salt forms, wherein the basic amine within the active moiety is reacted with a mineral acid, such as hydrochloric acid, to form the hydrochloride salt. Of course, other salt forms, such as citrates, tartrates, and sulfates as exemplified by fentanyl citrate, hydrocodone bitartrate, and morphine sulfate are also used, but these too form highly water soluble salts in nearly every conceivable physiologically environment. Their high water solubility also allows for drug product tampering wherein the active moiety can be removed from the drug product matrix, optionally concentrated, and then abused. For the purposes of the instant application, tampering is defined as the in vitro manipulation and extraction of the active ingredient, but not necessarily of the specific drug substance used in the drug product. The tampering may result in the isolation of the active ingredient as the free base or in a different salt form from that originally used in the drug product.
The societal, governmental, economic and moral demands placed on drug manufacturers to reduce the abuse potential of a drug product has captured the attention of national and state legislatures particularly with the United States Food and Drug Administration's controversial market approval of Zohydro®, an extended release hydrocodone bitartrate drug product absent of abuse deterrent functionality. This drug product is available in several strengths, which if used in the intended route of administration, provides for the extended release of hydrocodone. Unfortunately, with up to 50 mg of hydrocodone available to a potential abuser desiring to get high, and the product susceptible to tampering, (such as by simple water extraction of hydrocodone bitartrate) an abuser may readily obtain a life-threatening amount of the extracted drug substance. It is arguable if the benefits arising from an extended release hydrocodone product outweigh the inherent dangers of tampering associated with such a product. Indeed, it appears that this scenario is a repeat of the hard-won lessons learned concerning the abuse of extended release oxycodone products wherein tampering allowed for the isolation of the highly water soluble oxycodone hydrochloride.
The paradox for pharmaceutical manufacturers is the provision of medications that work as intended when the route of administration and dosage strength regimens are followed, but are otherwise difficult to abuse. A top-level analysis of this paradox suggests the two conditions are mutually exclusive. The physical and chemical properties which make a drug difficult to abuse are likely to prevent its desired physiological activity. For instance, isolation of the active ingredient from a formulated matrix, or tampering, requires differential solubility between the active ingredient, drug substance, and the other constituents, or excipients, of the drug product. In addition, the differential solubility must be achieved in solvent property ranges of protic to aprotic, and polar to non-polar solvents. This introduces almost limitless possibilities. Secondly, should drug product tampering result in the isolation of the drug substance, that material needs to be abuse deterrent and not susceptible to insufflation, or snorting, as a mechanism of abuse, possess release characteristics unfavorable for administration to other mucosal membranes and preferably the drug product should be unsuitable for preparation for injection preferably by impeding its ability to be delivered by syringe. The contradictions in product features and requirements continue when considering that abuse deterrence must not be thwarted by the potential abuser grinding, milling, crushing or chewing the product to otherwise make the active ingredient more available for mucosal absorption or for injection abuse. Lastly, while the manufacturer introduces physical and chemical barriers to prevent abuse of the drug product, the same drug product must still satisfy a patient's legitimate medical need.
An absolute solution to the above paradox may only have a practical solution wherein a technology is introduced that derails most attempts at tampering or insufflation abuse, imposes great difficulties for injecting the drug product or some combination of remaining constituents after tampering with the drug product formulation, or prevents drug substance absorption at mucosal membranes.
The FDA's attempts to address prescription drug abuse have included their Risk Evaluation and Mitigation Strategies (REMS) initiative. This initiative, while not limited to just opioid based medications, was principally enacted to address opioid pain medications formulated into extended release dosage presentations. The extended release (ER) dosage presentation might easily include sufficient opioid to relieve patient pain for up to twenty-four hours, or commonly, a sufficient dosage for twelve hours. The opiate content of the ER products could represent multiple dosages of the comparable immediate release (IR) drug products. The availability of the ER products to potential drug abusers was cause for great alarm, and cause of many deaths, when the abuser could manipulate or dose dump an ER tablet and achieve a rapid “high” from an exceptionally high dose of opiate available all at once.
Pamoate salts, and derivatives thereof, have been demonstrated as a suitable platform for the formation of abuse and dose-dumping deterrent drug substances as exemplified in commonly assigned U.S. Pat. Nos. 8,211,905; 8,329,720; 8,338,444; 8,367,693; 8,476,291; 8,569,329; 8,569,330; 8,748,416; 8,846,766 and 8,921,386 each of which is incorporated herein by reference. These patents describe a large accumulation of work elucidating the features, advantages and benefits available from organic acid addition salts of amine containing pharmaceutically active species. More specifically, the organic acid family contains those salt forming compounds inclusive of bidentate pamoic acid derivatives. Also described throughout these patents is the ability to manipulate the amine content of pamoate derived salts in such a way that from 1:1 to 2:1 amine:pamoate salts are obtained. Similarly, mixed salts are obtained of the A-B-C variety wherein A is an amine-containing pharmaceutically active moiety, B is the pamoate derivative moiety and C can be selected from a variety of amine containing species selected from the group consisting of A, dissolution modifying species, hydrophilic or lipophilic adjustment species and the like. Further described therein is the ability to modify the amorphous or polymorphic characteristics of these compounds to achieve a desired dissolution profile or solubility parameter. The ability to predictably adjust pamoate salt stoichiometry and to ultimately achieve different morphologies introduces capability for engineering dissolution profiles of the drug substance of the pharmaceutically active amine as its pamoate derivative salt, and for inhibiting alternate routes of drug administration most often used for drug abuse. Though beneficial, the availability of 1:1 salts wherein the bidentate pamoate derivative has a free carboxyl group, thereby allowing for enhanced manipulation of the chemistry of the pamoate derivative salts, has been, heretofore, difficult to obtain.
The desire to predictably prepare 1:1 pamoate derivative salts of amine containing pharmaceutical active medications, despite the above setbacks, has been achieved and reported by Applicants in other disclosures. For instance, Applicants have demonstrated in commonly assigned U.S. Pat. No. 8,846,766 to King et al. the preparation of 1:1 methadone pamoate from methadone pamoate 2:1 salt by a solvent cracking technique wherein the 2:1 salt can be converted to the 1:1 salt by exposure to refluxing solvent. Alternatively, Applicants, in commonly assigned U.S. Pat. No. 8,653,065 to King et al., have produced both 1:1 imipramine pamoate and imipramine mono-triethylammonium pamoate 1:1:1 salt wherein the trimethylamine component has been used as a labile protecting group for the “open” carboxyl position while the other carboxyl of the pamoate is bound with an imipramine component. While these techniques are generally useful, particularly the ammonia or lower molecular weight amines as labile protecting groups, a more general route to 1:1 pamoate salts is still needed. This need arises from the interest in achieving different dissolution profiles for the 1:1 salts as may be dependent upon their morphology, or the ability to subsequently react the open position of the pamoate derivative with a dissolution modifying agent or other functional excipient to impede abuse, to improve drug substance compatibility with formulation components or techniques, and/or to improve drug substance stability.
In spite of extensive efforts, the art is still lacking salts of active pharmaceuticals, particularly 1:1 salts using bidentate pamoate derivatives wherein abuse deterrence is provided at the drug substance level and wherein the drug substances are less susceptible to dose dumping. A method for administering such salts, and drug products comprising the salts, are provided herein.
The bi-dentate characteristic of pamoate has also been observed by others and attempts are recorded throughout the literature to take advantage of this structural capacity. For instance, European Patent Application 0 137 600 [Stuart, et. al] filed Jul. 19, 1983, now abandoned, purports the preparation of morphine pamoate (1:1) salt by controlling the stoichiometry of reagents; ostensibly, two equivalents of morphine would yield the 2:1 salt with pamoic acid while only one equivalent of morphine would yield the 1:1 salt. Methodically replicating the experimental conditions described in the application failed to reproduce the analytical data reported by Stuart. Further, the analytical data included in the Stuart application supported the view that different compounds were prepared other than those proposed by Stuart. Nonetheless, morphine pamoate (1:1) salt was contemplated by Stuart, but the proposed stoichiometric relationship was not obtained.
The literature contains a more intensive foray into the preparation of 1:1 pamoate salts in U.S. Pat. No. 6,987,111 to Greco, et. al. Therein reported are experimental efforts directed toward the preparation of haloperidol pamoate 1:1, and aripiprazole pamoate 1:1. However, replication of the experimental conditions was performed in order to carefully assess the generality of preparing the 1:1 salts, but this effort was fruitless. Indeed, Greco's Example 1 was repeated, but instead of obtaining the expected haloperidol pamoate (1:1) salt, the haloperidol pamoate 2:1 salt was obtained. Within the experimental parameters left undefined by Greco, a further exploration was performed by Applicants to determine if the elusive 1:1 salt could be generated. Each perturbation still yielded the 2:1 salt. Upon further inspection, Greco reports yield data in Example 1 that is inconsistent with the stoichiometric possibility of obtaining the 1:1 salt. Additional characterization of the haloperidol pamoate 2:1 salt actually obtained by Applicants upon attempted replication of the Greco methodology can be found in the Experimental section herein.
Interestingly, and in contrast to the conflicting results above, Example 2 in Greco describes preparation of haloperidol pamoate 2:1 salt, and replicating this procedure multiple times yielded the following results: 1) a compound consistent with that found by Greco and, which when observed under magnification appeared to exist as geometrical plates, and 2) an amorphous 2:1 salt with slight crystallinity present. In fact, Claims 3 and 4 in Greco address haloperidol pamoates of either 1:1 or 2:1 stoichiometry as being “needles” or crystalline. In fact, Greco's FIG. 1 contains two SEM micrographs: one showing exclusively geometric plates, the other exclusively needles. No mention is made by Greco of obtaining an amorphous compound. Further, during repetitive trials and with reasonable experimental perturbations of Greco's method for preparing haloperidol pamoate 2:1 salt, no sample comprising any amount of needles was obtained. Finally, Applicants obtained a 1:1 haloperidol pamoate arising from modification of Greco's Example 2 which therein describes preparation of 2:1 haloperidol pamoate. The compound isolated by Applicants was consistent in structure assignment to 1:1 haloperidol pamoate through 1H-NMR; however microscopic assessment of its physical form (crystalline by PXRD) still did not match the forms disclosed by Greco's FIG. 1 micrographs. It is clear that Greco's methods—while contributing to the pathway for routine preparation of 1:1 pamoate salts—still did not provide a predictable synthetic route to these valuable compounds. Indeed, Applicants' attempted use of the Greco disclosure led to unexpected results, including but not limited to: a) an amorphous form of haloperidol pamoate 2:1 salt, and b) a more predictable route to preparing various 1:1 salts. Unfortunately, the scientific literature inclusive of references cited herein has purported to achieve an obvious result, but the analytical chemistry characterization of the isolated compounds from such endeavors indicates otherwise. Therefore, the invention disclosed herein resolves the issues associated with preparing the 1:1 pamoate salts and provides a more definitive utility for their use in modern pharmaceutical products.